Diabetes Upregulation of Cyclooxygenase 2 Contributes to Altered Coronary Reactivity After Cardiac Surgery

Abstract

Background We hypothesized that upregulation of inducible cyclooxygenase 2 (COX-2) contributes to altered coronary arteriolar reactivity early after cardioplegic arrest and cardiopulmonary bypass (CP/CPB) in patients with diabetes mellitus who are undergoing cardiac surgery. Methods The right atrial tissue samples of non-diabetes (ND), controlled diabetes (CDM), and uncontrolled diabetes (UDM) patients undergoing cardiac surgery were harvested before and after CP/CPB. Coronary arterioles (80 to 150 mm) were dissected from the harvested atrial tissue samples, cannulated, and pressurized. The changes in diameter were measured with video microscopy. The protein expression and localization of COX-1 and COX-2 were assayed by Western blot and immunohistochemistry. Results In the diabetes arterioles, bradykinin-induced relaxation response was inhibited by the selective COX-2 inhibitor NS398 at baseline (p < 0.05). This effect was more pronounced in UDM arterioles than CDM (p < 0.05). After CP/CPB, bradykinin-induced responses in all groups were inhibited by NS398, but this effect was more pronounced in the UDM patients (p < 0.05). The intensities of COX-2 staining of coronary arterioles and COX-2 protein levels in myocardium were higher in diabetes than nondiabetes at baseline (p < 0.05). The post-CP/CPB protein levels of the inducible COX-2 were significantly increased compared with pre-CP/CPB values in all groups (p < 0.05), whereas this increase was higher with diabetes than with ND (p < 0.05). Furthermore, these effects were more profound in UDM than CDM (p < 0.05). Conclusions Diabetes and CP/CPB are associated with upregulation in COX-2 expression in human coronary vasculature. Upregulation of COX-2 expression may contribute to bradykinin-induced coronary arteriolar relaxation in diabetic patients undergoing cardiac surgery.

Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass

“…These novel findings suggest that diabetes markedly enhances COX-2 activation in the peripheral microvasculature, indicating that COX-2 may play an important role in the vasodilation pathway involving bradykinin in the peripheral microcirculation early after CPB. Consistent with our previous study in the ischemic heart and coronary microvasculature, 10,11,16 we found upregulation of COX-2 protein expression in the skeletal muscle and peripheral arterioles in the diabetic patients at baseline. In addition to the Western blot experiments, immune-histochemical staining also detected enhanced skeletal muscle and vascular localization of COX-2 in diabetic patients.…”

“…16 In the present study, we observed that bradykinin-induced vasodilation of the skeletal muscle arterioles was partially via COX-2 activation in diabetic patients, but not in non-diabetic patients at baseline. Importantly, after CPB, bradykinin-induced relaxation response was inhibited in the presence of the selective COX-2 inhibitor NS398 in both ND, and DM arterioles, whereas this effect was more pronounced in the DM group.…”

“…10,11 Recently, we have also found that diabetes induces COX-2 upregulation in ischemic myocardium and coronary arterioles in the setting of cardioplegic arrest and reperfusion. 16 These findings suggest that upregulation of COX-2 expression may contribute to bradykinin-induced coronary arteriolar relaxation in diabetic patients undergoing cardiac surgery. However, it is not known whether diabetes and/or CPB may also affect COX-2 expression in the skeletal muscle.…”

COX2 and NOS3 gene polymorphisms in women with gestational diabetes

“…The COX2 and NOS3 gene polymorphisms alter COX2 and NOS3 gene expression, as well as cyclooxygenase and nitric oxide synthesis. Cyclooxygenase and nitric oxide are important mediators of the inflammatory response in diabetes . Low grade inflammation has been shown to play a significant role in the pathogenesis of GDM …”

“…Cyclooxygenase and nitric oxide are important mediators of the inflammatory response in diabetes. [23][24][25][26][27] Low grade inflammation has been shown to play a significant role in the pathogenesis of GDM. [3][4][5] Apgar (0-10) 9.9 ± 0.4 9.7 ± 1.0…”